Natural killer cell cytotoxicity of breast cancer targets is enhanced by two distinct mechanisms of antibody-dependent cellular cytotoxicity against LFA-3 and HER2/neu

Sarah A Cooley, Linda J. Burns, Tanya Repka, Jeffrey S Miller

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177 Scopus citations

Abstract

Treatment of advanced breast cancer with autologous stem cell transplantation is limited by a high probability of disease relapse. In clinical trials, interleukin 2 (IL-2) alone can expand natural killer (NK) cells in vivo and increase their cytotoxic activity against breast cancer cell lines, but this increase is modest. Understanding the mechanisms that mediate NK cell lysis of breast cancer targets may lead to improvements of current immunotherapy strategies. NK cells from normal donors or patients receiving subcutaneous IL-2 were tested in cytotoxicity assays against five breast cancer cell lines. The role of adhesion molecules and antibodies that interact through Fc receptors on NK cells was explored. NK cell lysis of breast cancer targets is variable and is partially dependent on recognition through ICAM-1 and CD18. While blocking CD2 slightly decreased cytotoxicity, contrary to expectations, an antibody against CD58 (the ligand for CD2), failed to block killing and instead mediated an increased cytotoxicity that correlated with target density of CD58. The CD58 antibody-enhanced killing was dependent not only on FcRγIII but also on CD2 and ICAM-1/CD18. To further elucidate the mechanism of this CD58 antibody-dependent cellular cytotoxicity (ADCC), another antibody was tested. Trastuzumab (Herceptin), a humanized antibody against HER2/neu, mediated potent ADCC against all the HER2/neu positive breast cancer targets. Unlike CD58 antibody-mediated ADCC, Herceptin ADCC was minimally affected by blocking antibodies to CD2 or ICAM- 1/CD18, which suggests a different mechanism of action. This study shows that multiple mechanisms are involved in NK cell lysis of breast cancer targets, that none of the targets are inherently resistant to killing, and that two distinct mechanisms of ADCC can target immunotherapy to breast cancer cells.

Original languageEnglish (US)
Pages (from-to)1533-1541
Number of pages9
JournalExperimental Hematology
Volume27
Issue number10
DOIs
StatePublished - Oct 1999

Bibliographical note

Funding Information:
The authors thank Jennifer Tessmer-Tuck and Cara Hummer for their excellent technical help, and Brad Anderson for his help with flow cytometry. This work was supported in part by National Institute of Health Grant PO1-CA-65493. S. Cooley was supported by grants from the American Cancer Society Margaret Mitchell Research Scholarship, the American Society of Hematology Medical Student Scholarship Award, and the Minnesota Medical Foundation. Dr. Burns was supported by a grant from the Department of Defense. We also acknowledge the support of the Order of the Eastern Star, the University of Minnesota Bone Marrow Transplant Research Fund, and the Fairview-University Medical Center.

Keywords

  • Antibody-dependent cellular cytotoxicity
  • Breast cancer
  • Immunotherapy
  • Interleukin 2
  • Natural killer cell

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